Heartworm disease-Ettinger Flashcards

Question

CLINICAL SIGNS The clinical signs of chronic HWD depend on the severity and duration of infection and, in most chronic cases, reflect the effects of the parasite on the pulmonary arteries and lungs and, secondarily, the heart. It is important to point out that the vast majority of dogs with HWI are asymptomatic. Historical findings in affected dogs variably include weight loss, diminished exercise tolerance, lethargy, poor condition, cough, dyspnea, syncope, and abdominal distension (ascites). Physical examination may reveal evidence of weight loss, split-second heart sound (13%), right-sided heart murmur of tricuspid insufficiency (13%), and cardiac gallop.[14] If right heart failure is present, jugular venous distension and pulsation typically accompanies hepatosplenomegaly and ascites. Cardiac arrhythmias and conduction disturbances are uncommon in chronic HWD (

Answer 1

CLINICAL SIGNS The clinical signs of chronic HWD depend on the severity and duration of infection and, in most chronic cases, reflect the effects of the parasite on the pulmonary arteries and lungs and, secondarily, the heart. It is important to point out that the vast majority of dogs with HWI are asymptomatic. Historical findings in affected dogs variably include weight loss, diminished exercise tolerance, lethargy, poor condition, cough, dyspnea, syncope, and abdominal distension (ascites). Physical examination may reveal evidence of weight loss, split-second heart sound (13%), right-sided heart murmur of tricuspid insufficiency (13%), and cardiac gallop.[14] If right heart failure is present, jugular venous distension and pulsation typically accompanies hepatosplenomegaly and ascites. Cardiac arrhythmias and conduction disturbances are uncommon in chronic HWD (

Answer 2

Ideally the diagnosis is made by routine evaluation prior to the onset of symptoms (i.e., HWD). Dogs in areas in which heartworms are endemic should undergo a heartworm test yearly, particularly if no heartworm preventative or if diethylcarbamazine is used (see later discussion of controversies). This was accomplished most commonly in the past by the microscopic identification of microfilariae on a direct blood smear, above the buffy coat in a microhematocrit tube, using the modified Knott test, or after millipore filtration. The accuracy of these tests, typically used for routine screening and for the diagnosis of suspected HWI, is improved by multiple testing. The modified Knott test and millipore filtration are more sensitive because they concentrate microfilariae, improving chances of diagnosis. The direct smear technique allows examination of larval motion, helping in the distinction of D. immitis from Dipetalonema reconditum (now termed Acanthocheilonema reconditum); other useful diagnostic criteria are included in Table 254-1. This distinction is important because the presence of the latter parasite does not require expensive and potentially harmful arsenical therapy, as does D. immitis. None of these tests can rule out HWI conclusively because of the potential for amicrofilaremic infections (5% to 67%) and the fact that false-negative results may occur, particularly if microfilarial numbers are small, a small amount of blood is collected, or direct smears are relied upon. The number of circulating microfilariae in the peripheral blood do not correlate well with the number of adult heartworms and therefore cannot be used to determine the severity of infection.

Answer 3

In most practices, microfilarial testing has been largely supplanted by (or supplemented with) immunodiagnostic antigen testing (i.e., enzyme-linked immunosorbent assay [ELISA], lateral flow immunoassay, and rapid immunomigration techniques; Table 254-2). The modified Knott test should always be performed, however, in antigen-positive dogs to determine microfilarial status and in instances when owners continue to use diethylcarbamazine as a preventative. Some veterinarians choose to combine the antigen and microfilarial tests. This practice is most useful in dogs receiving diethylcarbamazine or no preventative (macrolides typically render the dog amicrofilaremic). Up to 1% of infected dogs are microfilaria positive and antigen negative.

Answer 4

Immunodiagnostic Antigen Tests In dogs not having received macrolide preventative therapies, the prevalence of amicrofilaremic infections is 5% to 67% (typically 10% to 20%).[16] This may be observed in prepatent (young) infections, in single-sex infections, with immune-mediated destruction of microfilaria, and with drug-induced amicrofilaremia. Dogs receiving macrolide preventatives are typically amicrofilaremic. Hence immunodiagnostic tests are now regularly used for both screening and in cases suspected of having HWI. These tests have rapidly gained popularity because of their high sensitivity and specificity and ease of performance (see Table 254-2).[17-20] The weakness of these tests is that they detect antigen from adult female heartworms and hence will produce negative results during the first ≈6 (5 to 8) months of any infection, in all-male infections, and in infections with low female worm burdens.

Answer 5

In fact, in a recent study of the performance of three commercial test kits in detecting low worm burden (

Answer 6

Certain ELISA antigen tests are designed to quantitatively predict worm burdens, based on antigen concentrations. Semiquantitative ELISA (Snap Canine Heartworm PF) has been used to successfully predict antigen load and hence approximate worm burden. Rawlings and colleagues[22] have shown this to be useful in predicting thromboembolic complications, with dogs bearing greater worm burdens being more likely to experience such complications after adulticide. This application is most useful, however, in instances of low antigen concentration (suggesting low worm burden) because high antigen concentrations might be recognized when all or most worms are dead, having released a large amount of antigen into the circulation.

Answer 7

ELISA technology also allows determination of the efficacy of adulticide therapy. ELISA antigen concentration typically falls to undetectable levels 8 to 12 weeks after successful adulticide therapy, so a positive test persisting beyond 12 weeks posttherapy has been suggested to indicate persistent infection.[23] However, antigen tests may remain positive for longer periods, and this author does not assume a failure in adulticidal therapy unless the antigen test is positive 6 months after adulticidal therapy

Answer 8

As previously suggested, macrolide therapy with ivermectin, milbemycin oxime, moxidectin, and selamectin results in clearance of microfilaria within 6 to 8 months.[23-25] In addition, embryostasis may be permanent. Thus the use of direct smears, the modified Knott test, and the millipore filter (microfilarial tests) in dogs receiving monthly heartworm preventatives (macrolides) is inappropriate. Therefore the only effective testing modality in the ever-increasing number of dogs receiving monthly preventative is the use of antigen assays. A general approach to the diagnosis of HWI is demonstrated in Figure 254-4

Answer 9

Figure 254-4 An algorithmic approach to the diagnosis of heartworm infection in the dog.

Answer 10

Radiography Although not an effective screening test for HWI, thoracic radiography offers an excellent method for detecting HWD, for determining its severity, and for evaluating pulmonary parenchymal changes. Radiographic abnormalities, which develop relatively early in the disease course, are present in approximately 85% of cases. According to the study of 200 heartworm-infected dogs by Losonsky and colleagues,[26] radiographic features (Figure 254-5) include right ventricular enlargement (60%), increased prominence of the main pulmonary artery segment (70%), increased size and density of the pulmonary arteries (50%), and pulmonary artery tortuosity and “pruning” (50%). If heart failure is present, enlargement of the caudal vena cava, liver, and spleen, as well as pleural effusion, ascites, or both, may be evident. Thrall and Calvert[27] suggested that pleural effusion is uncommon in heart failure due to HWD, demonstrating that marked enlargement of the cranial lobar pulmonary artery was a more sensitive indicator of HWD-associated heart failure than enlargement of the caudal vena cava.

Answer 11

Thoracic radiographs obtained in the ventrodorsal projection are preferable for cardiac silhouette evaluation and ease, and they often minimize patient stress. However, the dorsoventral projection is superior for the evaluation of the caudal lobar pulmonary vessels that are considered abnormal if larger than the diameter of the ninth rib where the rib and artery intersect (Figure 254-6; see Figure 254-5). The cranial pulmonary artery is best evaluated in the lateral projection and should normally not be larger than its accompanying vein or the proximal one third of the fourth rib (Figure 254-7).

Answer 12

The pulmonary parenchyma can best be evaluated radiographically. With pneumonitis, the findings include a mixed interstitial to alveolar density, which is typically most severe in the caudal lung lobes (Figure 254-8). In eosinophilic nodular pulmonary granulomatosis, the inflammatory process is arranged into the interstitial nodules, associated with bronchial lymphadenopathy and, occasionally, pleural effusion. With pulmonary thromboembolism, the radiographic findings of coalescing interstitial and alveolar infiltrates, particularly in the caudal lung lobes, reflect the increased pulmonary vascular permeability and inflammation described previously (see Figure 254-13). Consolidation may accompany massive embolization, pulmonary infarction, or both.

Answer 13

Figure 254-8 Lateral thoracic radiograph obtained from a coughing dog with chronic heartworm disease. The diffuse interstitial to alveolar infiltrate is severe and represents eosinophilic pneumonitis. Cardiac and pulmonary arterial changes are less severe than seen in Figures 254-6, 254-7, and 254-13.

Answer 14

Electrocardiography Electrocardiography is useful in detecting arrhythmias but is generally insensitive in detection of cardiac chamber enlargement in HWD when compared with radiography and echocardiography. If radiography does not suggest HWD, it is unlikely that the electrocardiogram (ECG) will be useful in the absence of arrhythmias. With the exception of CS and heart failure, arrhythmias are rare (2% to 4%).[28] Nevertheless, the finding of a right ventricular enlargement pattern (see Chapter 235) is supportive evidence for HWD. Lombard and Ackerman[28] demonstrated that ECG abnormalities were present in 38% to 62% of dogs with moderate and severe echocardiographic changes of HWD, while Calvert and Rawlings[29] found that only 6% of 276 dogs with dirofilariasis had ECG changes of right ventricular enlargement. Calvert and Rawlings[30] also showed that the most sensitive ECG parameters for detection of HWD are lead II S waves deeper than 0.8 mv, mean electrical axis greater than 103 degrees, and greater than three ECG parameters of right heart enlargement. The latter ECG finding (>three criteria) is considered to be the most accurate. P-pulmonale (tall P waves, indicative of right atrial enlargement) is unusual in HWD.

Answer 15

Echocardiography Echocardiography is relatively sensitive in the detection of right heart enlargement because the right ventricular end-diastolic dimension and septal and right ventricular free wall thickness are all increased (Figure 254-9). Lombard reported abnormal (paradoxical) septal motion in 4 of 10 dogs with HWD. The ratio of left-to-right ventricular internal dimensions is a useful calculation, being reduced from a normal value of 3 to 4 to a mean value of 0.7 in dogs with HWD. In some instances, two-dimensional echocardiography can be used to demonstrate worms in the pulmonary artery (see Figure 254-26). Although heartworms can occasionally be demonstrated in the right ventricle, this method is insensitive except in dogs with CS or very heavy worm burdens because the worms infrequently inhabit this location.

Answer 16

Clinical Pathology Hematologic and serum chemical abnormalities, although of limited use in making a diagnosis of HWD, are frequently useful in providing supportive evidence and for evaluating concurrent disease processes that may or may not be related to HWD. Calvert and Rawlings[30] report that the dog with HWD in Georgia is typically found to have a low-grade, nonregenerative anemia (present in 10% of mildly to moderately affected dogs and up to 60% of severely affected dogs), neutrophilia (20% to 80% of cases), eosinophilia (≈85% of cases), and basophilia (≈60% of cases). Thrombocytopenia, which may be noted in chronic HWD, CS, and DIC, is most common 1 to 2 weeks after adulticidal therapy. In severe HWD, especially if heart failure is present, liver enzyme activities may be increased (10% of cases) and occasionally hyperbilirubinemia is noted. Azotemia, seen in only 5% of cases, may be prerenal in origin if dehydration or heart failure is present or may be secondary to glomerulonephritis. In 10% to 30% of cases, albuminuria is noted. If glomerular disease is severe, hypoproteinemia (hypoalbuminemia) has the potential to complicate the clinical picture. Not surprisingly, the most severe clinicopathologic findings are associated with the most severe clinical findings.

Answer 17

Evaluation of tracheobronchial cytology is at times useful, particularly in the coughing dog with eosinophilic pneumonitis, occult HWD, and minimal radiographic evidence of HWD. Microscopic examination reveals evidence of an eosinophilic infiltrate. In microfilaremic dogs, L1 may occasionally be detected in this manner. Abdominal fluid analysis in cases of congestive heart failure (CHF) typically reveals a modified transudate. Dogs with HWD and right heart failure have central venous pressure (CVP) that ranges from 12 to more than 20 cm H2O, but ascites develop at lower CVPs if hypoalbuminemia is present.

Answer 18

MEDICAL MANAGEMENT The medical management of HWI is complex because of the complicated parasite life cycle, the marked variability in clinical manifestations and severity of HWD, prophylactic considerations, adulticidal and microfilaricidal considerations, and the relative toxicity and complications associated with adulticidal therapy. For these reasons, the diagnosis, prevention, and treatment of HWI remain a challenge.

Answer 19

Prophylaxis Prevention of HWI is an obvious and attainable goal for the veterinary profession. Prevention failure results from ignorance on the part of owners as to the presence or potential severity of HWI, lack of owner compliance, or from inadequate instruction on preventative measures by the attending veterinarian.[1,32-34] Studies of owner compliance have revealed that approximately 55% of dog owners that use veterinary care purchase heartworm preventative, and enough medication is dispensed only to meet the needs of approximately 56% of those dogs. Hence the proportion of “cared for” dogs in the population that receive adequate heartworm prophylaxis is less than one third.[33] If one takes into consideration doses purchased but not administered and dogs that are never taken to a veterinarian, the percentage of protected dogs falls drastically. This was emphasized in North Carolina in 1999, when Hurricane Floyd caused extensive flooding and disruption in the poorest part of the state. Of dogs rescued from the floodwaters, 67% were infected with heartworms (personal communication, Dr. Kelli Ferris, North Carolina State University, 2003). In addition, evidence suggests that the veterinary profession is failing in its education of clients. New and colleagues,[35] upon questioning veterinary clients purchasing macrolide preventatives, found that 38% did not realize that their prescribed drug's spectrum was broader than solely preventing HWI.

Answer 20

Diethylcarbamazine Diethylcarbamazine (DEC), which long enjoyed popularity as the preventative of choice, has now been largely replaced by the safer and more convenient macrolide preventatives. This product is safe (only in amicrofilaremic dogs) and effective; however, it must be given daily, making owner compliance problematic. DEC is thought to kill L3 and early L4 tissue migrating larvae but only has a small temporal window of therapeutic efficacy, thus explaining the need for frequent administration. Preventative should be administered daily from the onset of mosquito season, continuously until 1 to 2 months after a killing frost. In some geographic regions, the persistence of mosquitoes dictates yearlong prophylaxis, although this is controversial for much of the United States (see discussion of controversies, following). DEC must only be administered to dogs free of microfilariae, thus dictating a yearly heartworm test prior to reinstitution of preventative therapy. Inadvertent administration of DEC to microfilaremic dogs produces an adverse, possibly immune-mediated reaction in approximately 30%.[36] Signs associated with this adverse drug reaction usually occur within 1 hour of medication and include depression, ptyalism, vomiting, diarrhea, weak pulse, pale mucous membranes with poor capillary refill time, and bradycardia. Subsequently some dogs may become recumbent, dyspneic, and tachycardic, and 18% of reactors succumb. Restated, 6% of microfilaremic dogs to which DEC is administered will die due an adverse reaction. Not infrequently, owners inadvertently miss one or more doses of DEC preventative. If 1 day of therapy is omitted, no problem exists and drug administration should continue. In the event of a more prolonged lapse in DEC treatment, reinstitution of medication should be advised, with the realization that infection may have occurred during the prophylactic hiatus. These dogs should be reevaluated in 6 to 7 months to determine if infection has resulted. If a dog is found to be microfilaremic when receiving DEC, prophylaxis should be continued; however, if inadvertently stopped, reinstitution may result in the aforementioned adverse reaction.

Answer 21

Macrocyclic Lactone (Macrolide) Antibiotics The introduction of the macrocyclic lactone endectocides, ivermectin (Heartgard), milbemycin oxime (Interceptor), selamectin (Revolution), and moxidectin (ProHeart, ProHeart 6, and with imidicoprid in Advantage/Multi) has provided the veterinary profession with highly effective heartworm preventatives in a variety of formulations. These agents, because they interrupt larval development (L3 and L4) during the first 2 months after infection, have a large temporal window of efficacy and are administered monthly or less frequently. These agents are superior to DEC in convenience. Additionally, they produce less severe reactions when inadvertently given to microfilaremic dogs, allow a grace period (“reach-back,” “retroactive efficacy,” or “safety net”) for inadvertent lapses in administration, are more effective with treatment lapses of up to 2 to 3 months when used continuously for the next 12 months,[37] and have a dual role as microfilaricides.[20,37-39] Recently it has been shown that some macrolides have adulticidal activity if used continuously for prolonged periods.[39-41]

Answer 22

Ivermectin Ivermectin, a macrolide derived from avermectin B1 that is obtained from Streptomyces spp., is effective against a range of endoparasites and ectoparasites and is marketed as a once-monthly heartworm preventative. It is also marketed in a form with pyrantel pamoate to improve efficacy against intestinal parasites (hookworms and roundworms; Table 254-3). This combination product is safe in puppies as young as 6 weeks of age. Macrolides provide a wide window of efficacy and provide some protection when lapses in therapy occur (“reach-back”). Ivermectin is effective as a prophylactic with lapses of up to 2 months. Protection is extended, with continuous 12-month administration postexposure, with lapses of 3 months (98% efficacy) and of 4 months (95% efficacy).[37] As stated previously, ivermectin is microfilaricidal at preventative doses (6 to 12 µg/kg/month), resulting in a gradual decline in microfilarial numbers. Despite this gradual microfilarial destruction, generally mild, adverse reactions (transient diarrhea) can occur if administered to microfilaremic dogs.[37] Some breeds (Collies and Shetland Sheepdogs) are susceptible to ivermectin (and other macrolide) toxicosis at high doses, suffering neurologic signs. This has typically resulted with the use of concentrated livestock preparations, with clinical signs recognized with doses greater than 16 times the recommended dose.[25] For this reason, only preparations designed for pet use should be administered to dogs. When used appropriately, ivermectin is nearly 100% effective in preventing HWI. Additionally, recent studies have shown ivermectin to have adulticidal properties when used continuously for 16 months[40] and to be virtually 100% effective with continuous administration for 30 months.[41] (See later discussion of controversies.)

Answer 23

Milbemycin Milbemycin oxime is a nonmacrolide member of a family of milbemycin macrocyclic lactone antibiotics and is derived from a species of Streptomyces. At 500 to 999 µg/kg, it has efficacy against developing filarial larvae, arresting development in the first 6 weeks. It can therefore be given at monthly intervals with a “reach-back” effect of 2 months when doses are inadvertently delayed. With 12 months’ continuous treatment postexposure, this “safety net” can be extended to 3 months (97% efficacy), falling to 41% with lapses of 4 months.[37] At the preventative dose, milbemycin is a broad-spectrum parasiticide, being also effective against certain hookworms, roundworms, and whipworms (see Table 254-3) and can be initiated in puppies as young as 2 months of age. In microfilaremic dogs, milbemycin has greater potential for adverse reactions than do other macrocyclic lactones because it is a potent microfilaricide at preventative doses.[20] Adverse reactions, similar to those observed with ivermectin at microfilaricidal doses, may be observed in microfilaremic dogs receiving milbemycin at preventative doses.[42] As with microfilaricidal doses (50 µg/kg) of ivermectin, Benadryl (2 mg/kg intramuscularly) and dexamethasone (0.25 mg/kg intravenously) may be administered prior to milbemycin to prevent adverse reactions, particularly in dogs with high microfilarial counts. Milbemycin is also safe for use in Collies at the preventative dose. With appropriate use, milbemycin is nearly 100% efficacious as a heartworm prophylactic.

Answer 24

Moxidectin The macrolide preventative, moxidectin, has been more recently marketed as a narrow-spectrum (heartworm and hookworm) heartworm preventative (see Table 254-3) and shown to be safe and nearly 100% effective at 3 µg/kg orally, given monthly or bimonthly up to 2 months postinfection.[43] Oral moxidectin, at this dose, is gradually microfilaricidal and did not produce adverse reactions in a small number of microfilaremic dogs treated with the prophylactic dose.[38] At 15 µg/kg, 98% reduction in microfilarial numbers was documented 2 months posttreatment. Moxidectin appears to be safe in Collies[44] but cannot be administered orally to dogs

Answer 25

Selamectin Selamectin is a semisynthetic macrolide. It is unique in its broad spectrum and in the fact that it is applied topically once monthly (see Table 254-3). Its efficacy is similar to that of other macrolides (nearly 100%, when used as directed).[46] At 6 to 12 mg/kg topically, this preventative is effective at preventing heartworms infection and kills fleas and flea eggs, sarcoptic mange mites, ticks, and ear mites.[46] Bathing and swimming, as soon as 2 hours after application, does not alter efficacy. Safety has been shown at tenfold topical doses, with oral consumption of single doses and, in ivermectin-sensitive Collies, at recommended doses and fivefold overdoses for 3 months.[47] Like other macrolides, selamectin has at least a 2-month reach-back effect and with 12 months’ continuous administration is 99% protective after 3-month lapses in prophylaxis.[46],[48] Selamectin has slow microfilaricidal activity similar to other macrolides.[48] Selamectin can be administered to puppies as young as 6 weeks of age. Chronic, continuous selamectin administration has adulticidal efficacy, although no published data indicate that it is as effective in this role as ivermectin. In summary, the macrolides offer a convenient, effective, and safe method of heartworm prophylaxis with varying spectra and methods of administration (see Table 254-3). All are safe in Collies when used as directed at preventive dosages. They each have microfilaricidal efficacy and render female heartworms sterile. Hence microfilarial tests for HWI cannot be reliably used in dogs receiving these products. Prophylaxis should be commenced no later than 6 to 8 weeks of age in endemic areas or as soon thereafter as climatic conditions dictate.[19],[49] Although safer than DEC in microfilaremic dogs, before first-time administration any dog older than 6 months of age and at risk of infection should be tested (antigen test, followed by a microfilaria test, if antigen positive). Additionally, even though protective for at least 8 weeks postexposure, macrolides should be administered precisely as indicated by the manufacturer. If accidental lapses of more than 10 weeks occur, the preventative should be reinstituted at recommended doses and maintained for at least 12 consecutive months.[25] Macrolides can also be used to “rescue” dogs that have lapsed in their DEC daily therapy for up to 60 to 90 days.[19],[49] In the event of a lapse in preventative administration during a time of known exposure risk, an antigen heartworm test should be performed 7 to 8 months after the last possible exposure to determine if infection has occurred. The seasonal duration of protection required is controversial. The American Heartworm Society indicates that in colder climates, yearlong prevention “may not be” necessary,[54a] advocating beginning macrolides within 1 month of the anticipation of transmission season[25] and continuing 1 month beyond the transmission season.[19],[49] On the other hand, some experts (including the Companion Animal Parasite Council; www.CAPCvet.org ) believe that yearlong prevention should be embraced, regardless of geographic location.[50] This author advocates yearlong prevention, at the very least, below the Mason-Dixon line in North America. (See controversies section later.)

Answer 26

ADULTICIDAL THERAPY Melarsomine In most cases of HWD, it is imperative to rid the patient of the offending parasite. Thiacetarsemide, for decades the only drug approved for this purpose, is no longer available. It has been replaced by melarsomine (Immiticide), an organoarsenic superior in safety and efficacy to thiacetarsemide.[1] With two doses (2.5 mg/kg intramuscularly every 24 hours for 2 treatments), the efficacy is over 96%, with 99% efficacy with repeated two-dose therapy in 4 months or with the split dosage described later. Melarsomine has a mean retention time five times longer than thiacetarsemide, and its metabolites are free in the plasma (on which heartworms feed).[51],[52] In a study of 382 dogs with HWI receiving melarsomine, none required cessation of therapy due to hepatorenal toxicity (as compared with 15% to 30% with thiacetarsemide), and no case of severe PTE was observed.[53] Despite the enhanced safety of this product, adverse reactions are still noted.[14,16,54] In fact, successful pharmacologic adulticidal therapy, by definition, dictates thromboembolic events. The clinician can diminish the severity of this complication by restricting exercise after melarsomine administration. Perhaps the drug's biggest asset is the possibility of flexible dosing (“split-dose”—three [1, followed in no less than 30 days, by 2, the latter spaced by 24 hours] injections), allowing the potential for a safer 50% initial worm kill, followed by subsequent injections to approach 100% efficacy. Studies have shown that patients treated with the split-dose regimen have a higher seroconversion to a negative antigen status than patients treated with either caparsolate or the standard melarsomine dosing regimen.[55],[56] A split-dose protocol can be used in severely afflicted individuals or in those in which pulmonary thromboembolism is anticipated (Table 254-4). This method allows for destruction of only one half the worms initially (one intramuscular injection of 2.5 mg/kg), thereby lessening the chance for embolic complications. This single dose is followed by a two-dose regimen in 1 to 3 months, if clinical conditions permit. Although the manufacturer recommends this protocol for severely affected dogs, the author uses it for all cases unless financial constraint or underlying concern for arsenic toxicity exists (e.g., preexistent severe renal or hepatic disease; Figure 254-10).[54] Disadvantages to the split-dose method include additional expense, increased total arsenic dose, and the need for 2 months’ exercise restriction. In 55 dogs with severe HWD that were treated in this manner, 96% had a good or very good outcome with more than 98% negative for antigenemia 90 days posttherapy.[53] Of the 55 severely affected dogs, 31% had “mild or moderate PTE,” but no fatalities resulted. The most common sign was fever, cough, and anorexia 5 to 7 days posttreatment. This was associated with mild perivascular caudal lobar pulmonary radiographic densities and subsided spontaneously or after corticosteroid therapy.

Answer 27

Figure 254-10 An algorithmic approach to the management of heartworm infection in the dog. 

Answer 28

Microfilaricidal and Preventative Therapy in Heartworm-Positive Dogs At the time of diagnosis (usually by a positive heartworm antigen test) a minimum database is completed. This includes a microfilaria test, chemistry panel, complete blood count (CBC), urinalysis, and thoracic radiographic evaluation. If liver disease is suspected from clinical and laboratory findings, serum bile acid evaluation may be useful in evaluating liver function. At this time, monthly macrolide preventative is prescribed (see Figure 254-10).[54] This approach, which has been adopted by the American Heartworm Society,[54a] is used to prevent further infection, to eliminate microfilariae (chronic therapy renders the dog of no further risk to infect itself or other dogs and cats), and to destroy developing L4 (not yet susceptible to adulticidal therapy). In microfilaremic dogs, the first macrolide dose is administered in the hospital or at home, with observation, so an adverse reaction might be recognized and treated promptly. Corticosteroids with or without antihistamines (dexamethasone at 0.25 mg/kg intravenously and Benadryl at 2 mg/kg intramuscularly; or 1 mg/kg of prednisolone orally 1 hour before ± 6 hours after administration of the first dose of preventative) may be administered to reduce the potential for adverse reaction in highly microfilaremic patients. It is important to emphasize that adverse reactions are unusual with macrolides at preventative doses but caution should be exercised, particularly with milbemycin oxime. Depending on the time of year, up to 2 to 3 months might be allowed to lapse before adulticidal therapy is administered. Although monthly macrolide administration prevents further infection, this delay allows larval maturation to adulthood, ensuring that the only stage of the life cycle present is the adult, which is vulnerable to melarsomine therapy. This is more important if the diagnosis is made during or at the end of a mosquito exposure season. If the diagnosis is made in the spring or late winter, when infective larvae have matured, adulticidal therapy may be immediately administered (see Figure 254-10).

Answer 29

Procedure In the author's clinic, a nonsteroidal antiinflammatory drug is given the morning of the injection and continued for a total of 4 days in most cases. The first injection of melarsomine is administered by deep intramuscular injection (2.5 mg/kg) in the lumbar musculature (as described in the package insert) and the injection site recorded. Before injection, the needle is changed and care is taken to inject deep into the muscle and nowhere else. Patients are typically, but not necessarily, hospitalized for the day. The need for exercise restriction for 1 month is emphasized, and sedation is provided if necessary. Owners are also advised as to adverse reactions (fever, local inflammation, lassitude, inappetence, cough, dyspnea, collapse), to call if they have concerns, and to return for a second series of two injections in approximately 1 month. If serious systemic reaction results, the second stage of the adulticidal treatment is delayed or occasionally even canceled. Typically, however, even with severe reactions, the entire treatment protocol is completed within 2 to 3 months (see Figure 254-10). After a minimum of 1 month, the melarsomine injection procedure is repeated, again with a record of the injection site. If significant local reaction was noted after the first injection, subsequent injections are accompanied by dexamethasone and/or oral nonsteroidal antiinflammatory drugs to minimize pain at the injection site. The next day (approximately 24 hours after the first injection) the process is repeated with melarsomine injection into the opposite lumbar area. Client instructions are similar to those previously given, with reemphasis of the need for 1 months’ strict restriction of exercise. Antigen testing is repeated 6 months after the second series of injections, with a positive test result indicating incomplete adulticidal efficacy. It is emphasized that despite the proven efficacy of melarsomine, not all worms are killed in every patient. The worm burden is typically markedly reduced, but if as few as one to three adult female worms remain, positive antigen tests are likely. Whether to repeat adulticidal therapy, under these circumstances, is decided on a case-by-case basis with input from the owners.

Answer 30

Macrolides It is now known that certain macrolides have adulticidal properties.[39-41] Ivermectin, when administered monthly for 31 consecutive months, has nearly 100% adulticidal efficacy in young HWIs.[41] Selamectin, when administered continuously for 18 months, killed approximately 40% of transplanted worms.[39] Milbemycin and sustained-release moxidectin appear to have minimal adulticidal efficacy.[39],[40] Although there may be a role for this therapeutic strategy in cases in which financial constraints or concurrent medical problems prohibit melarsomine therapy, the current recommendations are that macrolides not be adapted as the primary adulticidal approach (see discussion of controversies, following).

Answer 31

Exercise Restriction Cage rest is an important aspect of the management of HWD after adulticidal therapy, after PTE, or during therapy of heart failure. This can often be best, or only, accomplished in the veterinary clinic. If financial constraints preclude this, crating or housing in the bathroom or garage at home, tranquilization, or both, with only gentle leash walks are useful alternatives. Nevertheless, some owners do not or cannot restrict exercise, resulting in or worsening thromboembolic complications.

Answer 32

Surgical Therapy Sasaki, Kitagawa, and Ishihara[57] have described a method of mechanical worm removal using a flexible alligator forceps (Figure 254-11). This method was 90% effective in 36 dogs with mild and severe HWD. Only two of the severely affected dogs (n = 9) died of heart and renal failure over 90 days postoperatively. These data suggest that, in skilled hands, the technique is safe. Subsequent studies by Morini and colleagues[58] demonstrated superior results as compared with melarsomine, producing less PTE and CS. It is important to note that the majority of dogs treated surgically required subsequent melarsomine administration to effect a cure. Advantages to this technique include its diminished potential arsenic toxicity (subsequent adulticidal therapy would be administered to an asymptomatic dog) and relative freedom from thromboembolic complication. Disadvantages include the need for general anesthesia, a degree of operator skill, fluoroscopy, and subsequent arsenic administration. Nevertheless, it remains a potential alternative for the management of high-risk patients.

Answer 33

ANCILLARY THERAPY Corticosteroids The antiinflammatory and immunosuppressive effects inherent to corticosteroids are useful for treatment of some aspects of HWD. Prednisone, the steroid most often advocated, reduces pulmonary arteritis but actually worsens the proliferative vascular lesions of HWD, diminishes pulmonary arterial flow, and reduces the effectiveness of thiacetarsemide. For these reasons, corticosteroids are indicated in HWD only in the face of pulmonary parenchymal complications (eosinophilic pneumonitis, eosinophilic granulomas, and PTE) to treat or prevent adverse reactions to microfilaricides and possibly to minimize tissue reaction to melarsomine. For allergic pneumonitis, prednisone (1 mg/kg/day) is administered for 3 to 5 days and discontinued or tapered as indicated.[9],[16] The response is generally favorable. Prednisone has also been advocated, along with cage rest, for the management of PTE at 1 to 2 mg/kg per day, continued until radiographic and clinical improvement is noted.[16] Because of the potential for steroid-induced fluid retention, such therapy should be used cautiously in the face of heart failure. In addition, caution is warranted because early studies demonstrated that postadulticidal corticosteroid therapy reduced pulmonary blood flow and worsened intimal disease in a model of HWI[59]; corticosteroids are also procoagulant.[16] As mentioned with adulticidal (previously discussed) and microfilaricidal (discussed following) therapies, corticosteroids may be used to minimize potential adverse reactions to melarsomine and to macrolides given to rapidly kill microfilariae

Answer 34

Aspirin Antithrombotic agents have received a good deal of attention in the management of HWD.[59-63] Potential benefits include reduction in severity of vascular lesions, reduction in thromboxane-induced pulmonary arterial vasoconstriction and PHT, and minimization of postadulticidal PTE.[61] Aspirin has shown success in diminishing the vascular damage caused by segments of dead worms,[61] reducing the extent and severity of myointimal proliferation caused by implanted living worms,[62] and improving pulmonary parenchymal disease and intimal proliferation in dogs receiving thiacetarsemide after previous living heartworm implantation.[59] More recent studies, however, have produced controversial results. Four dogs with implanted heartworms, receiving adulticide and administered aspirin, showed no improvement in pulmonary angiographic lesions, and treated dogs had more severe tortuosity than did controls and dogs receiving heparin.[60] Boudreau and colleagues[63] demonstrated that the aspirin dosage required to decrease platelet reactivity by at least 50% was increased by nearly 70% with HWI (implantation model) and by nearly 200% with a model (dead worm implantation) of PTE. There were not significant differences in severity of pulmonary vascular lesions in aspirin-treated versus control dogs. For these reasons, the American Heartworm Society does not endorse antithrombotic therapy for routine treatment of HWD.[20] Calvert and colleagues[16] have, however, successfully used the combination of aspirin and strict cage confinement with adulticidal therapy for severe HWD. If used, aspirin is administered daily beginning 1 to 3 weeks prior to and continued for 4 to 6 weeks after adulticide administration. With protracted aspirin therapy, packed cell volume (PCV) and serum total protein should be monitored periodically. Aspirin is avoided or discontinued in the face of gastrointestinal (GI) bleeding (melena or falling PCV), persistent emesis, thrombocytopenia (

Answer 35

Heparin Therapy Low-dose calcium heparin has been studied in canine HWD and shown to reduce the adverse reactions associated with thiacetarsemide in dogs with severe clinical signs, including heart failure.[64] In this study, calcium heparin, administered at 50 to 100 IU/kg subcutaneously every 8 to 12 hours for 1 to 2 weeks before and 3 to 6 weeks after adulticidal therapy, reduced thromboembolic complications and improved survival, as compared with aspirin and indobufen. Dogs in both groups also received prednisone at 1 mg/kg/day. It is emphasized that this therapy has not been studied with melarsomine adulticidal therapy. Calvert and colleagues[16] advocate sodium heparin (50 to 70 U/kg) in dogs with thrombocytopenia, DIC, or both, continuing until the platelet count is greater than 150,000/mm3, for at least 7 days, and possibly for weeks.

Answer 36

Doxycycline With the realization that Wolbachia may contribute to the pathogenesis of HWI and the adverse reactions to spontaneous and pharmacologically induced worm death, efforts to clear Wolbachia are under study.[13a,63a,63b,63c] In experimental infections (jugular transplantation), it has been shown that a complex regimen of ivermectin (weekly at preventive dosages [i.e., 4× typical dosage]) and doxycycline (10 mg/kg/day in an interrupted treatment regimen for 14 of 36 weeks) for 36 weeks eliminated microfilariae within 8 weeks, reduced PTE after melarsomine therapy, and reduced heartworm burden compared with control dogs by 78% after 9 months’ therapy.[13a,63a,63b,63c] It should be recognized that this treatment regimen is preliminary, off-label, complex, and impractical. It does, however, demonstrate a potential role for wolbachicidal therapy with doxycycline or other drugs in HWI.

Answer 37

Microfilaricidal Therapy Despite the fact that no agent is approved by the Food and Drug Administration for the elimination of microfilaria, microfilaricidal therapy has traditionally been instituted 3 to 6 weeks after adulticide administration.[16],[25] The macrolides offer a safe and effective alternative to levamisole and dithiazanine. Microfilariae are rapidly cleared with ivermectin at 50 µg/kg (approximately eight times preventative dose) or milbemycin at 500 mg/kg (preventative dose), although this represents an extralabel use of ivermectin. Adverse reactions, the severity of which is likely related to microfilarial numbers, were observed in 6% of 126 dogs receiving ivermectin at the microfilaricidal dose.[65] Signs included shock, depression, hypothermia, and vomiting. With fluid and corticosteroid (dexamethasone at 2 to 4 mg/kg intravenously) therapy, all dogs recovered within 12 hours. One fatality, however, was observed 4 days after microfilaricidal therapy. Similar findings and frequency have been reported with milbemycin at the preventative dose.[42] Dogs so treated should be hospitalized and carefully observed for the day. Dogs less than 16 kg, harboring more than 10,000 microfilaria per milliliter of blood, are more apt to suffer adverse reactions.[61] Benadryl (2 mg/kg intramuscularly) and dexamethasone (0.25 mg/kg intravenously) can be administered prophylactically to prevent adverse reactions to microfilaricidal doses of macrolides. A slower microfilarial kill rate can also be achieved with ivermectin, and selamectin at preventative doses.[23,39,45,66] Using either the rapid or “slow kill” approach rids the patient of microfilariae and sterilizes the female heartworm. This author chooses an alternative approach (see Figures 254-4 and 254-10), beginning the administration of a macrolide preventative at the time of diagnosis, often days to weeks prior to adulticidal therapy.[54] This approach is simpler, safer, less expensive, invokes immediate protection from further HWI, and represents a labeled use for macrocyclic lactones. With the slow kill microfilaricides (ivermectin, moxidectin, or selamectin at preventative doses), little chance exists of an adverse reaction; however, the owner is warned of the possibility and advised to administer the medication on a day when he or she will be at home. If milbemycin is used, the first dose (preventive dosage) is administered in the hospital and may be preceded by administration of dexamethasone and Benadryl (as described previously in adulticidal therapy). Doxycycline with ivermectin (or, possibly, another macrocyclic lactone) may play a future role in hastening the elimination of microfilariae as indicated earlier.

Answer 38

COMPLICATIONS AND SPECIFIC SYNDROMES Asymptomatic Heartworm Infection Most dogs with HWI are asymptomatic, even though many of these have HWD (radiographic and pathologic lesions). Treatment is as described previously, using melarsomine in the split-dose regimen, along with a macrolide preventative. Asymptomatic dogs may, however, become symptomatic after adulticidal therapy due to PTE and lung injury (as described elsewhere). The risk of PTE can be imperfectly predicted by semiquantitation of the worm burden, using certain antigen tests, and by the severity of radiographic lesions.[22] Clearly a dog with severe radiographic lesions will not tolerate thromboembolic complications well, but not all dogs with radiographic signs have heavy worm burdens. For example, a dog with moderate to severe radiographic lesions and high antigenemia may not be at high risk for postadulticidal PTE, because it is quite possible that the worms have died, explaining both the antigenemia (release from dead worms) and radiographic abnormalities (chronic HWD). This conclusion might also be valid in the dogs with severe radiographic lesions and negative or low antigenemia (assumes most or all worms have died, and antigen has been cleared). Alternatively, antigenic evidence of a heavy worm burden in a dog with minimal radiographic signs might still portend a severe reaction after melarsomine because the findings are compatible with large worm numbers but without natural worm attrition (i.e., a relatively young infection with minimal disease). Of course, low worm burden and minimal radiographic lesions would suggest the least risk of an adverse reaction to adulticide. It bears emphasis that with each scenario, guesswork is involved and precautions should be taken. When the risk is greatest, aspirin (5 to 7 mg/kg daily, begun 3 weeks prior to and continued until 3 weeks after adulticide) or even heparin may be used,[16] and cage confinement is most important. The owners should be educated as to the risk, the suggestive signs, and the importance of prompt veterinary assistance in case of an adverse reaction.

Answer 39

Glomerulonephritis The majority of dogs suffering from chronic HWI have glomerulonephritis, which can be severe (Figure 254-12).[11] Therefore when a dog demonstrates glomerular disease, HWI should be considered as a differential diagnosis. Although it is generally felt that the glomerular lesions produced by HWI are unlikely to produce renal failure, a therapeutic dilemma results when one is found in a dog with proteinuria, azotemia, and HWI. Logic suggests that adulticidal therapy is indicated because HWI contributes to glomerular disease, but it likewise carries risks. The approach embraced by this author is to hospitalize the patient and to administer intravenous fluids (lactated Ringer's solution at 2 to 3 mL/kg/hr) for 48 hours (beginning 12 hours prior to the first melarsomine dose). The patient is then released, and a recheck appointment for blood urea nitrogen (BUN) and creatinine determination after 48 hours is advised. The second and third injections are tentatively scheduled for 1 to 3 months, with the treatment decision based on renal function and the overall response to initial adulticidal therapy.

Answer 40

Allergic Pneumonitis Allergic pneumonitis, which is reported to affect 14% of dogs with HWD, is a relatively early development in the disease course.[9],[16] In fact, the pathogenesis probably involves immunologic reaction to dying microfilariae in the pulmonary capillaries. Clinical signs include cough and sometimes dyspnea and other typical signs of HWD, such as weight loss and exercise intolerance. Specific physical examination findings may be absent or may include dyspnea and audible crackles in more severe cases. Radiographic findings include those typical of HWD with an interstitial to alveolar infiltrate, often worse in the caudal lung lobes (see Figure 254-8). Eosinophils and basophils may be found in excess in peripheral blood and in airway samples. Corticosteroid therapy (prednisone or prednisolone at 1 to 2 mg/kg per day) results in rapid attenuation of clinical signs, with radiographic clearing in less than a week. The dose can then be stopped in 3 to 5 days if clinical signs subside. Although microfilaricidal therapy is typically not indicated because infections are often occult, macrocyclic lactone prophylaxis is indicated to avoid further infection. Adulticidal therapy can be used after clinical improvement.

Answer 41

Eosinophilic Granulomatosis A more serious, but rare, manifestation, pulmonary eosinophilic granulomatosis, responds less favorably. This syndrome is characterized by a more organized, nodular inflammatory process, associated with bronchial lymphadenopathy and, occasionally, pleural effusion. With pulmonary granulomatosis, cough, wheezes, and pulmonary crackles are often audible; when very severe, lung sounds may be muffled and associated with dyspnea and cyanosis. Treatment with prednisone at twice the dose for allergic pneumonitis is reported to induce partial or complete remission in 1 to 2 weeks. The prognosis remains guarded because recurrence within several weeks is common. Prednisone may be combined with cyclophosphamide or azathioprine in an effort to heighten the immunosuppressive effect. The latter combination appears to be the most effective. Adulticide therapy should be delayed until remission is attained. Because the prognosis for medical success is guarded, surgical excision of lobar lesions has been advocated

Answer 42

Pulmonary Embolization Spontaneous thrombosis or PTE associated with dead and dying worms—the most important heartworm complication—may precipitate or worsen clinical signs, producing or aggravating PHT, right heart failure or, in rare instances, hemoptysis and pulmonary infarction. Acute fatalities may result from fulminant respiratory failure, exsanguination, or DIC, or they may be unexplained and sudden (arrhythmia or massive pulmonary embolism). The most common presentation, however, is a sudden onset of lethargy, anorexia, and cough 7 to 10 days after adulticidal therapy, often after failure to restrict exercise. Dyspnea, fever, mucous membrane pallor, and adventitial lung sounds (crackles) may be noted on physical examination. Thoracic radiographs (Figure 254-13) reveal significant pulmonary infiltrates, most severe in the caudal lung lobes. The degree of worsening, as compared with pretreatment radiographs, is typically dramatic. The infiltrate, usually alveolar, is most severe in the caudal lobes, and occasionally areas of consolidation are noted. Laboratory abnormalities vary with the severity of signs but may include leukocytosis, left shift, monocytosis, eosinophilia, and thrombocytopenia. The degree of thrombocytopenia may provide prognostic information.

Answer 43

Medical management of thromboembolic lung disease is largely empiric and somewhat controversial. It is generally agreed that strict cage confinement, oxygen administration via oxygen cage or nasal insufflation (50 to 100 mL/kg/min), and prednisolone (1 mg/kg/day for 3 to 7 days) are indicated in the most severe cases.[14,16,68] Some advocate careful fluid therapy (see recommendations for CS), measuring CVP to avoid precipitation of heart failure, to maximize tissue perfusion and combat dehydration.[68] The use of heparin (75 IU/kg subcutaneously three times a day until platelet count has normalized [5 to 7 days]) and aspirin (5 to 7 mg/kg/day) has been advocated by some[30] but remains controversial.[4]

Answer 44

Other therapeutic strategies might include cough suppressants, antibiotics (if fever is unresponsive), and, although speculative at this time, vasodilators (amlodipine, sildenafil, hydralazine, diltiazem; see discussion of heart failure in Chapters 238 and 240).[69],[70] If vasodilatory therapy is used, one must monitor blood pressure because hypotension is a potential side effect. Clinical improvement may be rapid and release from the hospital considered after several days’ treatment. For less severely affected dogs, careful confinement and prednisone at home are often adequate.

Answer 45

Congestive Heart Failure Right heart failure results from increased right ventricular afterload (secondary to chronic pulmonary arterial disease and thromboemboli with resultant PHT). When severe and chronic, PHT may be complicated by secondary tricuspid regurgitation and right heart failure. Congestive signs (ascites) are worsened in the face of hypoproteinemia (Figure 254-14). Calvert suggests that up to 50% of dogs with severe pulmonary vascular complication to HWD will develop heart failure.[16] Clinical signs (see Figure 254-13) variably include weight loss, exercise intolerance, ashen mucous membranes with prolonged capillary refill time, ascites, dyspnea, jugular venous distension and pulsation, arrhythmias with pulse deficits, and adventitial lung sounds (crackles and possibly wheezes). Dyspnea may be due to pulmonary infiltrates (PIE or PTE, but not cardiogenic pulmonary edema), abdominal distension, or pleural effusion.

Answer 46

Treatment aims include reduction of signs of congestion, reducing PHT, and increasing cardiac output. This involves dietary, pharmacologic, and procedural interventions. Moderate salt restriction is logical and probably useful in diminishing diuretic needs. This author chooses a diet designed for senior patients or early heart failure, because salt restriction should only be moderate. Diuretics may be useful in preventing recurrence of ascites but are typically not able to mobilize large fluid accumulations effectively. This then requires periodic abdominal or thoracic paracentesis (or both) when discomfort is apparent. Furosemide is typically used at 1 to 4 mg/kg daily, depending on severity and patient response. Additional diuretics, which provide a supplemental effect by using differing parts of the nephron, include spironolactone (2 mg/kg orally once daily) and hydrochlorothiazide (1 to 2 mg/kg orally daily to every other day). The ACE-inhibitors (e.g., enalapril, benazepril, lisinopril, ramipril), by their effect on the renin-angiotensin-aldosterone system, may be of use as mixed vasodilators, in blunting pathologic cardiac remodeling and in reducing fluid retention, particularly cases of refractory ascites. Adulticide therapy is delayed until clinical improvement is noted. No evidence indicates that digoxin improves survival in HWD. Because of the risk of toxicity and pulmonary vasoconstriction associated with its use, it is not routinely used by the author in the management of HWD-induced heart failure. However, digoxin may be beneficial in the presence of supraventricular tachycardia or refractory heart failure. Aspirin, theoretically useful because of its ability to ameliorate some pulmonary vascular lesions and vasoconstriction, may be used 5 mg/kg/day orally.

Answer 47

The arterial vasodilator, hydralazine, has been shown by Lombard[69] to improve cardiac output in a small number of dogs with HWD and heart failure. It has also been demonstrated to reduce pulmonary artery pressure and vascular resistance, right ventricular work, and aortic pressure without changing cardiac output or heart rate in dogs with experimental HWD (but without heart failure).[70] Clinical experience has shown perceived improvement with the vasodilators diltiazem and amlodipine as well. Research and clinical experience suggest that hydralazine, amlodipine, sildenafil, and diltiazem might have a role in this setting, but further studies are necessary to define their role, if any. In heart failure the author uses hydralazine at 0.5 to 2 mg/kg orally twice a day, diltiazem at 0.5 to 1.5 mg/kg orally three times a day or a long-acting formulation uptitrated to 2 to 4 mg/kg once to twice daily orally, sildenafil at 0.5 to 1.0 mg/kg once to twice daily orally, or amlodipine at 0.1 to 0.25 mg/kg once daily orally. The risk of hypotension with these therapies must be realized and blood pressure monitored. In the author's practice, the inodilator pimobendan (0.25 mg/kg twice daily orally) has been employed in the treatment of heart failure due to HWD in a small number of cases, with variable success. The role of this drug in HWD remains to be clarified.

Answer 48

Often heart failure follows adulticidal therapy, but if it is present prior to adulticidal therapy, the difficult question arises as to when (or whether) to administer melarsomine. If clinical response to heart failure management is good, adulticidal therapy may be offered in 4 to 12 weeks, as conditions allow. Melarsomine is generally avoided if heart failure is refractory. Antiarrhythmic therapy is seldom necessary, although slowing the ventricular response to atrial fibrillation with digoxin, diltiazem, or both (see Chapters 238 and 240) may be necessary in some cases.

Answer 49

Caval Syndrome Heartworm CS is a relatively uncommon but severe variant or complication of HWD. Most studies have shown a marked sex predilection, with 75% to 90% of CS dogs being male. It is characterized by heavy worm burden (usually >60, with the majority of the worms residing in the right atrium and venae cavae) and a poor prognosis.[18] Studies performed in the author's laboratory indicate that retrograde migration of adult heartworms to the cavae and right atrium, from 5 to 17 months after infection, produces partial inflow obstruction to the right heart and, by interfering with the valve apparatus, tricuspid insufficiency (with resultant systolic murmur, jugular pulse, and CVP increase).[71] Affected dogs also exhibit preexistent heartworm-induced PHT, which markedly increases the adverse hemodynamic effects of tricuspid regurgitation. These combined effects substantially reduce left ventricular preload and hence cardiac output. Cardiac arrhythmias may further compromise cardiac function. (Figure 254-15).

Answer 50

This constellation of events precipitates a sudden onset of clinical signs, including hemolytic anemia caused by trauma to red blood cells (RBCs) as they pass through a sieve of heartworms occupying the right atrium and venae cavae, as well as through fibrin strands in capillaries if DIC has developed. Intravascular hemolysis, metabolic acidosis, and diminished hepatic function with impaired removal of circulating procoagulants contribute to the development of DIC. The effect of this traumatic insult to the erythron is magnified by increased RBC fragility, due to alterations in the RBC membrane in dogs with HWD. Hemoglobinemia, hemoglobinuria, and hepatic and renal dysfunction also are observed in many dogs.

Answer 51

passive congestion, diminished perfusion, and the deleterious effects of the products of hemolysis.

Answer 52

Without treatment, death frequently ensues within 24 to 72 hours due to cardiogenic shock, complicated by anemia, metabolic acidosis, and DIC. A sudden onset of anorexia, depression, weakness, and occasionally coughing are accompanied in most dogs by dyspnea and hemoglobinuria. Hemoglobinuria has been considered pathognomonic for this syndrome.

Answer 53

Physical examination reveals mucous membrane pallor, prolonged capillary refill time, weak pulses, jugular distension and pulsation, hepatosplenomegaly, and dyspnea. Thoracic auscultation may disclose adventitial lung sounds; a systolic heart murmur of tricuspid insufficiency (87% of cases); loud, split S2 (67%); and cardiac gallop (20%). Other reported findings include ascites (29%), jaundice (19%), and hemoptysis (6%). Body temperature varies from subnormal to mildly elevated.[18]

Answer 54

Figure 254-15 Schematic demonstrating pathogenesis of cardiac dysfunction in heartworm caval syndrome (CS). CS complicates chronic heartworm disease when retrograde worm migration from the pulmonary arteries occurs, with the majority of worms relocating in the venae cavae and right atrium. Tricuspid valvular function is altered, resulting in incompetence. Tricuspid regurgitation is superimposed on pulmonary hypertension. Left ventricular preload is diminished. Congestive and low-output heart failure ensues. Septal deviation to the left and abnormal, rightward septal motion contributes to preload starvation of the left ventricle. Right ventricular inflow obstruction due to heartworms and cardiac arrhythmias may further contribute to cardiac dysfunction but are probably less important. APC, Atrial premature complex; CO, cardiac output; CVP, central venous pressure; LVV, left ventricular volume; PAP, pulmonary hypertension; RAE, right atrial enlargement; RVE, right ventricular enlargement; RVH, right ventricular hypertrophy; RVP, right ventricular pressure; VPC, ventricular premature complex; arrows, increased or decreased. (From Atkins CE: Pathophysiology of heartworm caval syndrome: recent advances. In Otto GF: Proc Amer Heartworm Symposium 1989, Batavia, Ill, 1990, American Heartworm Society, pp 27-31.)

Answer 55

Hemoglobinemia and microfilaremia are present in 85% of dogs suffering from CS.[18] Moderate (mean PCV, 28%) regenerative anemia characterized by the presence of reticulocytes, nucleated RBC, and increased mean corpuscular volume (MCV) is seen in the majority of cases. This normochromic, macrocytic anemia has been associated with the presence of target cells, schistocytes, spur cells, and spherocytes. Leukocytosis (mean white blood cell [WBC] count, approximately 20,000 cells/cm3) with neutrophilia, eosinophilia, and left shift has been described.

Answer 56

Dogs affected with DIC are characterized by the presence of thrombocytopenia and hypofibrinogenemia, as well as prolonged one-stage prothrombin time (PT), partial thromboplastin time (PTT), activated coagulation time (ACT), and high fibrin degradation product concentrations.

Answer 57

Serum chemistry analysis typically discloses increases in liver enzymes, bilirubin, and indices of renal function. Urine analysis reveals high bilirubin and protein concentrations in 50% of cases and, more frequently, hemoglobinuria.

Answer 58

CVP is high in 80% to 90% of cases (mean, 11.4 cm H2O). Electrocardiographic abnormalities include sinus tachycardia in 33% of cases and atrial and ventricular premature complexes in 28% and 6%, respectively. The mean electrical axis tends to rotate rightward (mean, +129 degrees), with an S1,2,3 pattern evident in 38% of cases. The S wave depth in CV6LU (V4) is the most reliable indicator of right ventricular enlargement (>0.8 mv) in 56% of cases.

Answer 59

Thoracic radiography reveals signs of severe HWD with cardiomegaly, main pulmonary arterial enlargement, increased pulmonary vascularity, and pulmonary arterial tortuosity recognized in descending order of frequency (see Figures 254-5 to 254-7).

Answer 60

Massive worm inhabitation of the right atrium with movement into the right ventricle during diastole is evident echocardiographically. This finding on M-mode and two-dimensional echocardiograms is nearly pathognomonic for CS in the appropriate clinical setting (Figure 254-16). The right ventricular lumen is enlarged and the left diminished in size, suggesting PHT accompanied by reduced left ventricular loading. Paradoxical septal motion, caused by high right ventricular pressure, is commonly observed. No echocardiographic evidence of left ventricular dysfunction exists.

Answer 61

Cardiac catheterization documents pulmonary, right atrial, and right ventricular hypertension and reduced cardiac output.

Answer 62

Figure 254-16 An M-mode echocardiogram of a dog with recent onset caval syndrome, demonstrating thickening of the right ventricular and intraventricular septal walls, right ventricular eccentric hypertrophy, and a small left ventricle. An echogenic mass (clear arrow) of heartworms can be seen “falling” into the right ventricle with each diastole. Paradoxical septal motion is evident. The white arrow denotes the pericardium. i, Intraventricular septum; l, left ventricular lumen; L, left ventricular posterior wall; R, right ventricular wall; r, right ventricular lumen. (From Atkins CE: Heartworm caval syndrome. Semin Vet Med Surg 2:64-71, 1987.)

Answer 63

Prognosis is poor unless the cause of the crisis—the right atrial and caval heartworms—is removed. Even with this treatment, mortality can approximate 40%. Fluid therapy is necessary to improve cardiac output and tissue perfusion, to prevent or help to reverse DIC, to prevent hemoglobin nephropathy, and to aid in the correction of metabolic acidosis. Overexuberant fluid therapy, however, may worsen or precipitate signs of CHF. In the author's clinic, a left jugular catheter is placed and intravenous fluid therapy instituted with 5% dextrose in water or one-half strength saline and 2.5% dextrose. The catheter should not enter the anterior vena cava because it will interfere with worm embolectomy. A cephalic catheter may be substituted for the somewhat inconvenient jugular catheter, but this does not allow monitoring of CVP. The intravenous infusion rate for fluids is dependent on the condition of the animal. A useful guideline is to infuse as rapidly as possible (up to 1 cardiovascular volume during the first hour) without raising the CVP or without raising it above 10 cm H2O if it was normal or near normal at the outset. Initial therapy should be aggressive (10 to 20 mL/kg/hr for the first hour) if shock is accompanied by a normal CVP (

Answer 64

The technique for surgical removal of caval and atrial heartworms was developed by Jackson and colleagues.[72] This procedure should be undertaken as early in the course of therapy as is practical. Often, sedation is unnecessary, and the procedure can be accomplished with only local anesthesia. The dog is restrained in left lateral recumbency after surgical clipping and preparation. The jugular vein is isolated distally. A ligature is placed loosely around the cranial aspect of the vein until it is incised, after which the ligature is tied. Alligator forceps (20 to 40 cm, preferably of small diameter) are guided gently down the vein while being held loosely between the thumb and forefinger. The jugular vein can be temporarily occluded with umbilical tape. If difficulty is encountered in passage of the forceps, gentle manipulation of the dog by assistants to further extend the neck will assist in passage of the forceps past the thoracic inlet; medial direction of the forceps may be necessary at the base of the heart. Once the forceps have been placed, the jaws are opened, the forceps are advanced slightly, the jaws are closed, and the worms are removed. One to four worms are usually removed with each pass. This process is repeated until five to six successive attempts are unsuccessful. An effort should be made to remove 35 to 50 worms. Care should be taken not to fracture heartworm during extraction. After worm removal, the jugular vein is ligated distally, and subcutaneous and skin sutures are placed routinely. Other catheters, such as urethral stone basket catheters, horsehair brushes, snares and flexible alligator forceps, have also been used.[73] Fluoroscopic guidance, when available, is useful in this procedure. Successful worm retrieval is associated with a reduction in the intensity of the cardiac murmur and jugular pulsations, absence of HW echo shadows on ultrasound examination, rapid clearing of hemoglobinemia and hemoglobinuria, and normalization of serum enzymatic aberrations. Immediate and latent improvement in cardiac function occurs over the next 24 hours. It is important to realize that removal of worms does nothing to reduce right ventricular afterload (PHT), and hence fluid therapy must be monitored carefully before and after surgery to avoid precipitation or worsening of right heart failure. Cage rest should be enforced for a period of time suitable for individual care.

Answer 65

Worm embolectomy through a jugular venotomy is frequently successful in stabilizing the animal, allowing adulticide therapy to be instituted to destroy remaining heartworms in a minimum of 1 month. Careful scrutiny of BUN and serum liver enzyme concentrations should precede the latter treatment. Aspirin therapy is continued for 3 to 4 weeks after adulticide therapy. Substantial improvement in anemia should not be expected for 2 to 4 weeks after worm embolectomy. Macrolide preventative therapy, as described previously, is administered at the time of release from the hospital.

Answer 66

Aberrant Migration Although heartworms in the dog typically inhabit the pulmonary arteries of the caudal lung lobes, they may find their way to the right ventricle, and rarely (see Caval Syndrome earlier) the right atria and venae cavae. Much less frequently, immature L5 may aberrantly migrate to other sites, including the brain, spinal cord, epidural space, anterior chamber of the eye, the vitreous, the subcutis, and the peritoneal cavity. In addition, the worms may inhabit the systemic circulation, producing systemic thromboembolic disease.[12] Treatment of aberrantly migrating heartworms requires either nothing (e.g., peritoneal cavity), surgical excision of the offending parasite, adulticidal therapy, or symptomatic treatment (e.g., seizure control with brain migration). The method for surgical removal from internal iliac and femoral arteries has been described.[12]

Answer 67

PROGNOSIS The prognosis for asymptomatic HWI is generally good and, although the prognosis for severe HWD has to be guarded, a large percentage of such cases can be successfully managed.[74] Once the initial crisis is past and adulticidal therapy has been successful, resolution of underlying manifestations of chronic HWD begins. The prognosis is poorest with severe DIC, CS, massive embolization, eosinophilic granulomatosis, severe pulmonary artery disease, and heart failure. After adulticidal therapy, intimal lesions regress rapidly.[75-77] Improvement is noted as early as 4 weeks posttreatment in the main pulmonary artery, with all pulmonary arteries having undergone marked resolution within 1 year. Radiographic and arteriographic lesions of HWD begin to resolve within 3 to 4 weeks, and PHT is reduced within months and may be normal within 6 months of adulticide therapy. Pulmonary parenchymal changes are worsened during the 6 months after adulticidal therapy and then begin to lessen in severity, with marked resolution within the next 2 to 3 months. Persistence of such lesions is suggestive of ongoing infection. Corticosteroid therapy hastens the resolution of these lesions. Likewise, irreversible renal disease is uncommon, with glomerular lesions resolving within months of successful adulticidal therapy. Signs of heart failure are also reversible with symptomatic therapy, cage rest, and successful clearing of infection.

Answer 68

CONTROVERSIES Yearly Testing The remarkable efficacy of macrolide preventatives and the reduced danger of microfilaria-induced reactions with their use (see following section on preventives), have caused some to question the need for yearly testing.[51] Many experts, however, continue to advocate this practice.[18] The issue of yearly testing is clearly important because it deals with financial and ethical, in addition to medical, issues. The veterinary profession must walk the fine line between adequate testing, by which we protect the public, and excessive testing, by which the public may feel “gouged.” This is difficult because only sparse scientific detail exists to answer this question, and the answer likely differs by geographic region and even within regions, based on socioeconomic strata and client compliance. Arguments can be put forth both for and against yearly testing.[18] Proponents might argue that this practice gets animals into the clinic yearly (vaccination may not [see Chapter 197]), thereby ensuring yearly examination and resultant health benefits and income, and provides inexpensive insurance against unrecognized infection caused by poor compliance or dogs that surreptitiously expectorate orally administered medications. In addition, yearly antigen testing is very specific (i.e., little risk of false-positive results), prevents long-term infections from becoming established during the period between heartworm checks, and would seem to limit liability to the practicing veterinarian. They might well also point out that recent reports have demonstrated poor compliance for heartworm prophylaxis nationwide,[32-34] and even though macrolide preventatives provide the safety net of the so-called reach-back effect (retroactive efficacy, safety net) discussed elsewhere, this benefit is realized only with lapses of less than 3 to 4 months, varies between products, and requires continuous administration for 1 year after the lapse.[37] Finally, yearly testing for heartworm antigen is useful to pick up latent (infections that have progressed too far to be eliminated with preventative but are not patent at the time that preventative was prescribed) or incompletely eradicated infections. On the other hand, the opponent of yearly testing might point out that if as a profession we emphasize the efficacy and importance of preventive agents, we may lose credibility by also promoting yearly testing. Additionally, the macrolide preventatives are very efficacious, possessing reach-back potential, in the hands of conscientious clients, and the risk of severe adverse reactions in dogs not known to be infected and receiving macrolides is small. The reason that adverse reactions are less likely is because most dogs will be rendered pharmacologically amicrofilaremic or will have small microfilarial burdens. In addition, the reactions to macrolides in microfilaremic dogs are less severe than to DEC. Furthermore, the argument can be made that the small worm burdens, most likely to result when preventative lapses are brief, will be minimally harmful and might even escape detection by immunologic tests, and that the chances of false-positive tests increase with low prevalence (as would be expected in a population of pets receiving preventative and yearly evaluation). The American Heartworm Society addressed this question in 1995.[78] It stated “ … after the initial retest, if it appears that monthly chemoprophylaxis is being given as prescribed, retesting at intervals greater than 1 year may be sufficient. However, reasonable doubt that administration has been adequate would justify retesting at shorter intervals, perhaps on an annual basis.” Unfortunately little data exist on owner compliance with preventatives, and the data that have been generated are alarming. Cummings and colleagues[33] surveyed dispensing records of 50 veterinary practices in heartworm-endemic areas in the United States and found that, based on the practices’ own recommendations, only enough medication was dispensed to adequately protect 41% of the canine clients. This was largely due to the fact that medication was dispensed for less than 50% of the dogs in the practices. It is important to add that this study did not identify compliance failure in which dispensed medications were not administered or in which administered medication was not applied or was not swallowed. These data suggest that the majority of our canine patients should undergo yearly testing. Positive test results in this population should be carefully scrutinized, however. In 2005, the American Heartworm Society stated, “As lack of efficacy has been reported for all macrocyclic lactones, annual retesting is an integral part of ensuring that prophylaxis is achieved and maintained” and the CAPC recommends annual testing.[54a]

Answer 69

YEARLONG PREVENTION Because of the necessity of the mosquito as an intermediate host for HWI, it has been logical and accepted practice to discontinue preventatives during the winter months in the more northern climates. In warmer climates, where mosquitoes may be encountered 12 months of the year, yearlong prophylaxis has been the practice. With the advent of monthly, very effective prophylactic agents, and with improved understanding of the temperature dependence of heartworm transmission by mosquitoes, this yearlong practice has been called into question.[3] Although no supportive data exist, it might be assumed that the ease of administration of monthly preventatives may improve owner compliance and that the reach-back effect will make up for short lapses in therapy or unexpected exposures at the beginning or end of the transmission season, thereby making the effective period of prevention longer. More importantly, studies have shown that transmission, even in heartworm-endemic areas, does not occur during the final quarter of the year.[2] This is because the mosquito, which is generally assumed to live 30 days, requires a minimum average daily ambient temperature to allow larval development to the infectious (L3) stage. This requirement is defined in heartworm development units (HDUs). An HDU is the degree days (in °C) that the average ambient temperature surpasses the developmental threshold of 14° C (57° F).[2] Restated, for each day that the average ambient temperature exceeds the threshold, an HDU is attained; if the average temperature is 16° C for 1 day, for example, then 2 HDUs are attained. For development of infective larvae, 130 HDUs must be attained and, to be effective, these must be attained in the lifetime of the female mosquito (≈30 days). If the average temperature is 16° C, for example, it would take 65 days for L3 to develop, thereby making transmission impossible. On the other hand, a 24° C average temperature would allow the molt to L3 to occur in 13 days, well within the mosquito's life expectancy. In a very innovative approach to this question, Knight and Lok[3] surveyed temperature extremes in 200 weather stations over a 30-year period and calculated the worst case scenario for transmission of heartworms. The resultant isotherm maps (Figure 254-17) constructed from this information indicate the month to begin and to cease heartworm preventative therapy by geographic region. In only Hawaii, southern Florida, and the southern tip of Texas is yearlong preventative deemed necessary, using this model.

Answer 70

• Do all female mosquitoes really live only 30 days? • Do some mosquito species live longer than others? • Are there not other climatic factors such as humidity that play a role in larval development? • Are there not microclimates within isotherm regions that might allow more HDUs to be attained? • Might not mosquitoes seek microclimates (indoors perhaps) with temperatures to allow heartworm larval development?

Answer 71

Third, owner compliance has been shown to be less than optimal.[32-34] Fourth, the macrolide reach-back effect, which protects dogs for which compliance is imperfect, is less than 100% after a maximum 4-month lapse in therapy, varies among preventatives, and requires 12 to 14 months of continuous therapy after the lapse to be effective.[37] Additionally, should an adult infection be present, macrolide adulticidal efficacy requires at least 2 years’ continuous therapy.[41] Fifth, sometimes significant differences exist in adjacent isotherm regions, rendering decision making confusing and potentially hazardous. For example, in Florida, adjacent regions exist that require 10 or 12 months of preventative treatment. How does an owner or veterinarian know which protocol to use? Furthermore, in some areas, the change from current recommendations to those based on the isotherm maps is minimal. For example, in Wisconsin, current seasonal recommendations would dictate starting heartworm preventative in May and continuing through November, whereas the isotherm map suggests July through October, a difference of two doses. Sixth, animals travel, often to warmer climates during “nontransmission” seasons. Seventh, because some macrolides and macrolide combination drugs have broad spectra, their use in other parasite control might argue for their use for longer than just the projected heartworm transmission season. Lastly, the savings to clients is relatively small. If a client in North Carolina (January 2009) goes from yearlong prevention to the Knight-Lok recommendation (12-month administration to 7-month administration), the savings for a 25-lb dog is about $30 per year.

Answer 72

The Knight-Lok model has provided new and useful information, indicating that the risk in other than prime heartworm season is less than previously believed, and that in some instances heartworm prophylaxis is excessive. The Knight-Lok model should stand as a suggestion for the timing of prophylaxis, with practice erring to the conservative. This means extending the isotherm map suggestion 1 month in either direction and taking the earliest implementation date and the latest cessation date surrounding one's geographic region. As a profession, we are faced with the dilemma of providing the best care with fiscal responsibility. The fact that our previous assumptions have come under some reassessment should be brought to the clients’ attention, using the points made previously. It then falls upon the shoulders of the client to determine if the risk of possible, but generally unlikely, infection is worth the savings.

Answer 73

• Represents an off-label use of ivermectin • Requires continuous compliance from a client who often has allowed HWI to occur—often by poor compliance • Lack of knowledge about the timing and degree of exercise restriction necessary; safe use might require 31 months of continuous exercise restriction • Absence of a controlled kill as seen with melarsomine, reducing the ability to effectively monitor for adverse effects • Lack of knowledge as to the effect of chronic antigen release from slowly dying adult heartworms on the kidneys and lungs • Knowledge that macrolide “slow adulticidal therapy” does not alleviate the lung disease associated with HWI[79] • Fact that proven efficacy is only in young (

Answer 74

At the 2001 American Heartworm Symposium, the audience and a panel of experts were polled about their beliefs as to the role of ivermectin as an adulticide in their own practices.[80] Five percent of the audience and none of the expert panelists used only ivermectin for adulticidal therapy. Approximately one third of both groups did not or would not use ivermectin as an adulticide under any circumstances. Finally, approximately 70% of the expert panel and 50% of the audience stated that they would use ivermectin for this purpose only under mitigating circumstances of financial or medical constraint.

Answer 75

The author recommends that melarsomine be the primary adulticidal tool and recommends or accepts the use of ivermectin in instances where a preventative is necessary in a heartworm-positive dog and the owner cannot afford arsenic therapy or in which medical conditions preclude its use; in the event of residual infection after appropriate treatment with melarsomine (assumes low worm burden); and, obviously, in unrecognized infections.

Answer 76

ANTI-Wolbachia THERAPY The interactions of Wolbachia, filarid parasites, and their hosts, as well as the use of doxycycline therapy, has been reviewed by McCall and associates.[3a] The use of doxycycline to destroy Wolbachia, which lives in a symbiotic relationship within the HW, is logical at a number of levels. It is possible that the HW would be debilitated or killed, that larval development might be inhibited, that HW fertility and transmission would be lessened, that adulticidal efficacy of melarsomine and/or ivermectin might be enhanced, that immune-mediated pathology (e.g., glomerulonephritis) might be reduced, and that the pathology produced by living or dead/dying worms and Wolbachia might be lessened. To date, publication of the use of doxycycline in the treatment of natural HWI is sparse.[81] In experimental (jugular transplantation) infections, it has been shown that doxycycline at 10 mg/kg/day for 14 of 36 weeks, coupled with weekly ivermectin at preventive dosages (i.e., fourfold increase over label dosage), reduces the number of microfilariae more quickly than ivermectin alone, reduced melarsomine-induced PTE, and sped “soft-kill” of adult heartworms using ivermectin, but not adulticidal effects of melarsomine.[13a,63a,63b,63c] It should be pointed out that current data do not demonstrate whether the off-label reduced dosing interval (weekly) of ivermectin or the use of doxycycline has provided the described benefit, that there are no data on efficacy in natural infections, that the exact protocol is far from understood, and that doxycycline is not without side effects.[82] This author, nevertheless, combines doxycycline (10 mg/kg/day) with monthly ivermectin for soft-kill (when used) and uses doxycycline (along with macrolide preventive) to attempt to reduce melarsomine-associated PTE (10 mg/kg/day for 1 month after diagnosis, and twice for 2 weeks after each melarsomine treatment).

Answer 77

FELINE HEARTWORM DISEASE LIFE CYCLE The life cycle of D. immitis is similar in the cat and the dog (see Figure 254-2). Feline HWI infection differs in that cats are not generally the preferred target for feeding mosquitoes; that to be an effective vector for cats a mosquito has to have first fed on a canid; and that, as an unnatural host, cats are inherently resistant to HWI. Infections in cats therefore tend to be relatively infrequent and small. In addition, the life cycle takes longer in the cat, such that patency (noted in

Answer 78

The distinction between HW exposure (L3, L4, and immature L5 [immature adult] infection) and HWI (typically thought of as mature L5 or mature adult infections) has become more complex and important with recent discoveries. We now know that cats which are “exposed” to HW, but reject the infection at the young adult (immature L5) stage, still develop respiratory lesions in an estimated 50% of cases. This increases our estimate of the percentage of cats that develop mature HWI or heartworm-associated lesions by 5 to 10 times (i.e., both those cats with mature and immature/aborted infections, the latter 5 to 10 times more common).

Answer 79

The recognition that aborted immature infections produce disease has led some experts in the field to term all exposed, antibody-positive cats (with or without adult heartworms) as being “infected.” In the current publication, I will specify mature HWI for adult infections and will refer to aborted infections as “immature infections” or “exposure,” with the acknowledgement that such cats may develop lung disease from their exposure (“HARD” or “pulmonary larval dirofilariasis”).

Answer 80

The domestic cat, though an atypical host, can be parasitized by D. immitis, with resultant HWD. The clinical manifestations of the disease are different and often more severe in this species, but if one considers mature infections only, the infection rate is only 5% to 20% of that of the dog.[85] Experimental infection of the cat is more difficult than in the dog; less than 25% of L3 reach adulthood. This resistance is also reflected in natural infections, in which feline heartworm burdens are usually less than 10 and typically only 1 to 4 worms.[86] Other indications of the cat's inherent resistance to this parasite are a shortened period of worm patency, high frequency of amicrofilaremia or low microfilaria counts, and shortened life span of adult heartworms (previously thought to be 2 to 3 years, with new evidence suggesting that it is longer in natural infections—up to 4 years).[87],[90] Nevertheless, studies have shown a mature HWI prevalence as high as 14% in shelter cats[1] and a study performed on well-cared-for cats in Texas and North Carolina revealed mature HWD in 9 of 100 cats with cardiorespiratory signs.[88] Furthermore, antibody testing showed 26% of these cats had been “exposed” to HWI.[88] Recent studies have failed to support the belief that males were at greater risk for natural HWI.[92] Aberrant worm migration appears to be a greater problem in cats than in dogs.

Answer 81

It is important to clarify the distinction between mature HWI (adult HW living in pulmonary arteries, or elsewhere) and aborted infections (“exposure” without parasite maturation). Immature L5 may create pulmonary and pulmonary vascular disease in cats prior to maturation. Uniquely, the disease process develops even in cats that ultimately resist the mature infection, and clinical signs and disease antedate clinicians’ ability to diagnose the disease through conventional means. Studies have shown that radiographic lesions develop in experimentally infected cats and pulmonary vascular lesions develop in naturally infected cats in which maturation of immature adults does not occur. Furthermore, experimental infections, pharmacologically aborted before HW maturation, have recently been shown to produce not only proliferative and inflammatory pulmonary arterial lesions, but proliferative and inflammatory disease of bronchioles and lung parenchyma as well.[89] Presumably, these findings are associated with the respiratory signs often seen in cats without mature HWI and have recently been termed “heartworm-associated respiratory disease” (HARD) or “pulmonary larval dirofilariasis.” These important studies showed that cats “exposed” (infected without allowing full HW maturation) to HW develop respiratory lesions and clinical signs of HWD. These findings are important in that they not only demonstrate that HWI that is ultimately rejected often produces clinical signs (asthmalike) and that many more cats develop signs of HWD than previously believed. This is because 38% to 74% of cats with mature HWI develop clinical signs, as do an estimated 50% of those that abort the infection (pulmonary larval dirofilariasis; estimated to be 5 to 10× as many as cats as with mature infections).[87],[90]

Answer 82

The pulmonary arterial response to adult (mature L5) heartworms is more severe in cats than in dogs (due, in part, to the presence of pulmonary intravascular macrophages), although PHT has been infrequently been reported. Dillon[4] demonstrated pulmonary enlargement within 1 week of transplantation of adults, suggesting an intense host-parasite interaction. A severe myointimal and eosinophilic response produces pulmonary vascular narrowing and tortuosity, thrombosis, and possibly hypertension (Figure 254-18).[11]

Answer 83

Because the feline pulmonary artery tree is smaller than that of the dog and has less collateral circulation, embolization, even with small numbers of worms, produces disastrous results with infarction and even death. Although uncommon, cor pulmonale and right heart failure can be associated with chronic feline HWD and is manifested by pleural effusion (hydrothorax or chylothorax), ascites, or both. The lung per se is also insulted by HWI, with eosinophilic infiltrates in the lung parenchyma (pneumonitis) and pulmonary arteries (Figure 254-19). The pulmonary vessels may leak plasma, producing pulmonary edema (possibly acute respiratory distress syndrome), and type II cells proliferate, both potentially altering O2 diffusion.[92] In addition, radiographic findings suggest air trapping, compatible with bronchoconstriction.

Answer 84

The end result to this multifaceted insult is diminished pulmonary function, hypoxemia, dyspnea, cough, and even death. Sudden death in heartworm-infected cats may involve an anaphylactic-like reaction to dying worms.[94] It is noteworthy that recent studies of natural asymptomatic feline HW infections in a hyperendemic region in Italy revealed that approximately 80% of infected cats self-cured.[87],[90]

Answer 85

Figure 254-18 H&E stain demonstrating large pulmonary artery with obstruction of lumen due to severe medial smooth muscle hypertrophy and hyperplasia, subintimal and intimal fibrosis, endarteritis, and possibly thrombosis. The reader should also note the periarterial interstitial (probably eosinophilic) pneumonia.

Answer 86

Figure 254-19 Small pulmonary artery from the cat seen in Figure 254-18 showing mild medial hypertrophy. The reader should note the extreme perivascular cuff of inflammatory cells around the vessel, representing an eosinophilic infiltrate.

Answer 87

CLINICAL SIGNS Clinical manifestations of HWD in cats may be peracute, acute, or chronic.[88,92,95-97] However, in a retrospective study, 28% of cats with mature HWI, seen at a referral center, were presented for signs not referable to HWI.[97] Furthermore, newer, prospectively derived data from two Italian studies of 77 cats seen in general practice revealed that only 58% of asymptomatic cats ultimately developed clinical signs of HWD with one third of these being fatal.[87],[90]

Answer 88

Acute or peracute presentation is usually due to worm death and/or embolization or aberrant migration, and signs variably include salivation, tachycardia, shock, dyspnea, hemoptysis, vomiting and diarrhea, syncope, dementia, ataxia, circling, head tilt, blindness, seizures, and death. Postmortem examination often reveals pulmonary infarction with congestion and edema.

Answer 89

More commonly, the onset of signs is less acute (chronic form). Reported historical findings in chronic feline HWD include anorexia, weight loss, lethargy, exercise intolerance, signs of right heart failure (pleural effusion; uncommon), cough, dyspnea, and vomiting. The author and colleagues have found dyspnea and cough to be relatively consistent findings and, when present, should cause suspicion of HWD in endemic areas.[97] Chylothorax and pneumothorax and CS have also been recognized as uncommon manifestations of feline HWD.

Answer 90

In a report of 50 natural cases of feline HWI in North Carolina, presenting signs were most commonly related to the respiratory system (32 cats; 64%), with dyspnea (24 cats; 48%) being most often noted, followed by cough (19 cats; 38%) and wheezing (Figure 254-20).[97] Vomiting was reported in 17 (38%) cats and was noted frequently in 8 (16%). Five (10%) heartworm-infected cats were reported to have exhibited vomiting without concurrent respiratory signs and vomiting was a presenting sign in seven (14%). Neurologic signs (including collapse or syncope [10%]) were reported in seven (14%) cats. Five (10%) of the cats were dead at the time of presentation. Murmurs were infrequently noted in cats that did not have concurrent heart disease, independent of HWI. Heart failure was present in one cat, but it had concurrent hypertrophic cardiomyopathy. HWI was considered to be an incidental finding in 14 (28%) of the cats in this study.

Answer 91

Physical examination is often unrewarding, although a murmur, gallop, or diminished or adventitial lung sounds (or a combination of these findings) may be noted. In addition, cats may be thin, dyspneic, or both. If heart failure is present, jugular venous distension, dyspnea, and rarely ascites are detected.

Answer 92

1. First, clinical signs are often absent, and when present, quite different from those of the dog. 2. In addition, the overall incidence in cats is low, so suspicion is lessened; eosinophilia is transient or absent; immunologic tests are often falsely negative; electrocardiographic findings are minimal; radiographic signs are inconsistent and transient; and most cats are amicrofilaremic. 3. Finally, the clinician must understand that antigen-positive cats nearly always have mature HWI and antibody-positive (antigen-negative) cats typically do not have mature HWI. However, approximately 50% of antibody positive/antigen negative cats develop HARD/pulmonary larval dirofilariasis. Because antigen tests continue to improve, their exact sensitivity is not known in cats but is estimated to be 50% to 75% in natural infections.

Answer 93

No compelling medical reasons exist to screen cats for HWI prior to administration of macrolide preventatives because the risk of adverse reactions associated with microfilarial death is small (cats are amicrofilaremic or have small microfilarial numbers, and adverse reactions are minimized with macrolide preventatives). Nevertheless, screening allows the clinician to alert pet owners if their cats have been exposed (antibody positive) so that they might pursue confirmation of the diagnosis of mature HWI, if they wish. It also minimizes public relations problems if the cat develops HWD while on preventative. In addition, routine screening allows the clinician to understand the risk of heartworm exposure in the practice area. The author's approach to routine screening of cats for heartworms differs somewhat from that when suspicion of infection exists (Figure 254-21).

Answer 94

Figure 254-21 A, Algorithm demonstrating the author's approach to the diagnosis of heartworm infection in cats in which infection is suspected. B, Algorithm demonstrating the author's approach to screening cats for heartworm infection. *, Thoracic radiographs and blood tests; †, exposure means that cat was exposed and allowed development to L4 stage, but may or may not have allowed parasite maturation. Some prefer to refer to this cat as infected, since the infection was probably eliminated at the immature L5 stage and clinical signs may be present.

Answer 95

Immunodiagnostic methods (see Table 254-2) are imperfect in cats because of the low worm burdens and hence, antigenic load. In one study, ELISA antigen tests on sera from experimentally infected cats were positive on sera from 36% to 93% of 31 cats harboring 1 to 7 female heartworms, with sensitivity increasing as female worm burden increased.[98] Cats with a male worm or worms were not detected as positive. Therefore false-negative tests occur frequently, depending on test used, maturity and gender of worms, and worm burden. All tests were, however, virtually 100% specific. It is important to realize that infection with signs may be present prior to the presence of detectable antigen (from gravid adult females). McCall and colleagues[99] report that, in natural infections, the antigen test detects less than 50% of cases. Snyder and colleagues[101] present differing data (from natural infections in which blood was obtained as long as 2 hours posteuthanasia) that show that the antigen test is more sensitive than previous reports (74%) indicated. An antigen test (IDEXX's SNAP Feline Heartworm Antigen Test) has been marketed for cats. This is an adaptation of the canine test, with a reported increase in sensitivity of 15% over conventional antigen tests

Answer 96

Although less specific for mature infections, heartworm antibody tests may be of use in the detection of feline HWI, even when antigen tests are negative. In a recent study of 1962 HW–antibody-positive cats, only 18.6% were antigen positive. The antibody test also serves as a marker for exposure to and risk of HWI (even if the cat never develops a mature infection) and for the possibility of pulmonary larval dirofilariasis (HARD). An in-clinic feline heartworm antibody test is also available (HESKA: Solo Step FH).

Answer 97

It is important to emphasize that it is estimated that half of antibody-positive, antigen-negative cats have postmortem manifestations of HWD and that in these cats, the antibody-positive state may wane with time. Often, the antibody test is used in conjunction with the antigen test; each is available in a cage-side and send-off format.

Answer 98

Thoracic radiographs have been suggested as an excellent screening test in cats. However, asymptomatic cats rarely have radiographic lesions.[90] Schafer and Berry[102] showed that the most sensitive radiographic criterion (left caudal pulmonary artery greater than 1.6 times the ninth rib at the ninth intercostal space on the ventrodorsal projection) was only detected in 53% of cases. Furthermore, even though most cats with clinical signs have some radiographic abnormality, the findings are not specific to HWD. In addition, a study by Selcer and colleagues[103] demonstrated that radiographic findings were often transient, and radiographic abnormalities were found in cats that ultimately resisted heartworm maturation and were negative on postmortem. Radiographic findings include enlarged caudal pulmonary arteries (Figure 254-22), often with ill-defined margins, pulmonary parenchymal changes that include focal or diffuse infiltrates (interstitial, bronchointerstitial, or even alveolar), perivascular density, and occasionally, atelectasis (Figures 254-23 and 254-24). Pulmonary hyperinflation may also be evident, and the misdiagnosis of feline bronchial disease can easily be made (see Figures 254-22, A, and 254-23, A). Pulmonary angiography has also been used to demonstrate radiolucent linear intravascular foreign bodies and enlarged, tortuous, and blunted pulmonary arteries (Figure 254-25).

Answer 99

Echocardiography, in the author's experience, is more sensitive in cats than in dogs.[88],[104] Typically, a double-lined echodensity is evident in the main pulmonary artery, one of its branches, the right ventricle, or occasionally at the right atrioventricular (AV) junction (Figure 254-26). The author and colleagues[88] found heartworms by echocardiography in 78% of nine cases, as did Selcer and colleagues[89] in 16 experimental infections

Answer 100

TREATMENT AND PREVENTION The question arises as to whether heartworm prophylaxis is warranted for cats because they are not the natural host and because the incidence is low. Necropsy studies of feline HWI in the Southeast have yielded a mature HWI prevalence of 2.5% to 14%, with a median of approximately 5% (Figure 254-27).[85] When considering the question of institution of prophylaxis, it is worth considering that this prevalence approximates or even exceeds that of feline leukemia virus (FeLV) and feline immunodeficiency virus (FIV) infections.[105] A 1998 nationwide antibody survey of over 2000 largely asymptomatic cats revealed an exposure prevalence of nearly 12% (Figure 254-28)[106] and has been suggested as being as high as 16%,[107] though other estimates have been lower (1% to 8%).[108] If we assume that a 12% antibody-positive rate indicates a prevalence of mature HWI of 1% to 2% and of 5% to 6% for HARD, then a nationwide feline morbidity (mature cases and HARD cases) associated with HWI might be expected to approach 6% to 8%). It is also noteworthy that, based on owners’ information, nearly one third of cats diagnosed with HWD at NCSU were housed solely indoors.[97] Lastly, the consequences of feline HWD are potentially dire, with no clear therapeutic solutions. Therefore the author advocates preventative therapy in cats in endemic areas.

Answer 101

Four drugs with FDA approval are marketed for use in cats (Table 254-5). Ivermectin is provided in a chewable formulation, milbemycin as a flavored tablet, and selamectin and moxidectin/imidacloprid (broad-spectrum endoparasiticides and ectoparasiticides) come in topical formulations. The spectrum and the formulation of these products vary; hence the clients’ individual needs are easily met in most cases (see Table 254-5).

Answer 102

Because the vast majority of cats are amicrofilaremic, microfilaricidal therapy is unnecessary in this species. The use of arsenical adulticides is problematic. Thiacetarsemide (sodium caparsolate), if available, poses risks even in normal cats. Turner, Lees, and Brown[109] reported death due to pulmonary edema and respiratory failure in 3 of 14 normal cats given thiacetarsemide (2.2 mg/kg twice over 24 hours). Dillon and colleagues[110] could not confirm this acute pulmonary reaction in 12 normal cats receiving thiacetarsemide, but one cat did die after the final injection. More importantly, a significant, though unquantified, percentage of cats with HWI develop pulmonary thromboembolism (PTE) after adulticidal therapy.[92-95] This occurs several days to 1 week after therapy and is often fatal. In 50 cats with HWI, seen at NCSU, 11 received thiacetarsemide. There was no significant difference in survival between those receiving thiacetarsemide and those receiving symptomatic therapy.[97]

Answer 103

Data on melarsomine in experimental (transplanted) HWI in cats are limited and contradictory. Although an abstract report exists in which one injection (2.5 mg/kg; one half the recommended canine dose) of melarsomine was used in experimentally infected cats without treatment-related mortality, the worm burdens after treatment were not significantly different from those found in untreated control cats.[111] Diarrhea and heart murmurs were frequently noted in treated cats. A second abstract report, using either the standard canine protocol (2.5 mg/kg twice over 24 hours) or the split dose (one injection, followed by two injections, 24 hours apart, in 1 month) gave more favorable results.[112] The standard treatment and split-dose regimens resulted in 79% and 86% reduction in worm burdens, respectively, and there were no adverse reactions. Although promising, these unpublished data need to be interpreted with caution because the transplanted worms were young (

Answer 104

The use of aspirin has been questioned because vascular changes associated with HWI consume platelets, increasing their turnover rate and effectually diminishing the antithrombotic effects of the drug. Conventional doses of aspirin did not prevent angiographically detected vascular lesions in experimental HWI.[113] Doses of aspirin required to produce even limited histologic benefit approached the toxic range. Because the quoted studies were based on relatively insensitive estimates of platelet function and pulmonary arterial disease (thereby possibly missing subtle benefits), because therapeutic options are limited, and because at conventional doses (40 to 80 mg orally, every 72 hours), aspirin is generally harmless, inexpensive, and convenient, the author continues to advocate aspirin for cats with HWI. Aspirin is not, however, prescribed with concurrent corticosteroid therapy. Management of other signs of HWD in cats is largely symptomatic.

Answer 105

PROGNOSIS In the aforementioned study of 50 cats with natural HWI, at least 12 cats died of causes other than HWD. Seven of these and two living cats were considered to have survived HWD (lived >1000 days).[97] The median survival for all heartworm-infected cats living beyond the day of diagnosis was 1460 days (4 years; range, 2 to 4015 days), whereas the median survival of all cats (n = 48 with adequate follow-up) was 540 days (1.5 years; range, zero to 4015 days). Survival of 11 cats treated with sodium caparsolate (mean, 1669 days) was not significantly different from that of the 30 managed without adulticide (mean, 1107 days). Likewise, youth (

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